Oral cancer accounts for approximately 2% of all cancers diagnosed in the United States. Despite advances in therapy, the 5-year survival of patients with oral cancer has not significantly improved in decades, largely because metastases are usually present when oral cancer is diagnosed. Antiangiogenic therapy, such as therapy against vascular endothelial growth factor (VEGF), has been suggested as a potential treatment for oral cancer. However, currently approved antiangiogenic drugs have prolonged overall survival by only a few months in patients with other types of cancer. Furthermore, emerging evidence from laboratory and clinical studies indicates that, although antiangiogenic therapy inhibits the growth of primary tumors, it may also promote tumor invasion and metastasis owing to a hypoxia-inducible factor (HIF-1)-mediated adaptive-evasive response to worsening tumor hypoxia after successful antiangiogenic therapy. Therefore, it appears that a combination of antiangiogenic drugs with anti-HIF-1 drugs would be promising. Approximately 90% of oral cancers are squamous cell carcinoma, a subtype associated with overexpression of epidermal growth factor receptor (EGFR). Cetuximab, an EGFR-blocking antibody, is approved by the FDA in combination with radiotherapy for head and neck cancers, including oral cancers. We recently reported that cetuximab can decrease HIF-11 in both normoxic and hypoxic cancer cells. In this exploratory/developmental project, we propose to develop a novel recombinant antibody that targets both VEGF and EGFR. Our hypothesis is that a recombinant antibody that can inhibit VEGF-induced angiogenesis and also decrease the HIF-11 level through inhibition of the EGFR pathway in oral cancer works better than single-agent therapy with approved anti-VEGF or anti-EGFR drugs. We will test the hypothesis in oral cancer cell models in which both VEGF and EGFR are important promoters of cancer cell growth, invasion, and metastasis. We will compare the antitumor effects of our recombinant antibody with those of the FDA-approved anti-VEGF antibody bevacizumab and the FDA- approved anti-EGFR antibody cetuximab in terms of the impact on invasion and metastasis in metastatic oral cancer xenografts. We expect the proposed work to lead to development and validation of a novel recombinant antibody that not only inhibits growth of primary tumors but also prevents antiangiogenic therapy-induced invasion and metastasis. Such a novel recombinant antibody may significantly improve the 5-survival rate for patients with oral cancer through successful prevention and treatment of metastatic disease.